Substituted 2-bromo-2-nitro-alkyl esters of salicylic acid

ABSTRACT

NOVEL SALICYLIC ACID ESTERS OF THE FORMULA   2-(R1-C(-BR)(-NO2)-CH(-R)-OOC-)PHENOL   WHEREIN R IS SELECTED FROM THE GROUP CONSISING OF HYDROGEN, METHYL AND HALOGENATED METHYL, AND R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL AND ETHYL WHICH MAY BE SUBSTITUTED WITH AT LEAST ONE HYDROXY GROUP WHICH HAVE ANTIMICROBIC ACTIVITY AND LOWER TOXICITY THAN THE CORRESPONDING FREE ALCOHOLS.

United States Patent Olfice 3,651,124 Patented Mar. 21, 1972 3,651,124 SUBSTITUTED Z-BROMO-Z-NITRO-ALKYL ESTERS OF SALICYLIC ACID Richard Wessendorf, Essen-Heisingen, and Horst Bellinger, Dusseldorf, Germany, assignors to Henkel & Cie.,

GmbH, Dusseldorf-Holthausen, Germany No Drawing. Filed Oct. 22, 1970, Ser. No. 83,235 Claims priority, application Germany, Nov. 6, 1969,

Int. Cl. C07c 69/88 US. Cl. 260-474 6 Claims ABSTRACT OF THE DISCLOSURE Novel salicvlic acid esters of the formula O R Br -ii--eH-em l IO wherein R is selected from the group consisting of hydrogen, methyl and halogenated methyl and R is selected from the group consisting of hydrogen and methyl and ethyl which may be substituted with at least one hydroxy group which have antimicrobic activity and lower toxicity than the corresponding free alcohols.

STATE OF THE ART The antimicrobial activity of many salicylic acid derivatives such as 3,4,S-tribromosalicylanilide and other halogen and trifluoromethyl substituted salicylanilides and combinations of these compounds, is known. In many cases, the said compounds possess a suflicient activity, but their spectrum of action has not been found satisfactory, since besides having a strong fungicidal action, a very good killing of gram-positive as well as gram-negative bacteria is also required at very. low concentrations of the active material. Compounds are also known generally as antimicrobial substances which contain bromo and nitro groups, especially aliphatic bromonitro-alcohols, in which the bromide atom and the nitro group are attached to the same carbon atom. Besides a very high antimicrobial activity, the latter compounds such as 2-bromo-2-nitropropanediol-(1,3) or especially l-bromo-l-nitro-3,3,3-trichloropropanol-(Z), have also a very broad spectrum of action. In some cases, however, the high toxicity of the compounds becomes noticeably troublesome.

OBJECTS OF THE INVENTION The novel salicylic acid esters of the invention have the formula O R Br Jim-balm.

wherein R is selected from the group consisting of hydro gen, methyl and halogenated methyl and R is selected from the group consisting of hydrogen and methyl and ethyl which'may besubstituted with at least one hydroxy group. The halogenated methyl group of R may have 1 to 3 halogens such as chlorine, bromine, etc. The novel esters of the invention have the advantage of low toxicity while keeping the entire antimicrobial activity of the corresponding free bromonitro alcohol and in some cases the said activity is enhanced.

Examples of suitable salicylic acid esters of the invention are 2-bromo-2-nitro-ethyl salicylate, 2-bromo-2-nitropropyl salicylate, 2-bromo-2-nitro-l-trichloromethylethyl salicylate, 2-bromo-2-nitrobutyl salicylate, 2-bromo-2- nitro-l-methyl-propyl salicylate and 2-bromo-2-nitro-3- hydroxypropyl salicylate.

The preparation of the said bromonitroalkyl esters of salicylic acid may be effected in known ways such as by reacting a bromonitro-alcohol with salicylic acid chloride in an inert organic solvent such as benzene or carbon tetrachloride. The salicylic acid chloride needed for the reaction is obtainable in 94% yield from salicylic acid and thionyl chloride by known methods. The bromonitro-alcohols to be used can be prepared as follows.

A nitroalcohol formed from a nitroalkane and an aldehyde can be converted into the sodium salt of the desired nitro-alcohol by reaction with sodium alcoholate in alcoholic solution, which salt is then reacted with bromine in an organic solvent such as ether, chloroform or carbon tetrachloride to give a bromonitroalcohol. The 1-nitro-3,3, 3-trichloropropanol-(2) formed by condensation of chloral with nitromethane by the process described in the Journal Chem. Soc. (1935), p. 1178, may be reacted with sodium methylate to give the corresponding sodium salt and then brominated to 1-bromo-1-nitro-3,3,3-trichloropropanol-(Z). A further possibility for the preparation of bromonitro-alcohols is to react an aldehyde, a nitroalkane and an inorganic magnesium or alkaline earth salt in the presence of water and to brominate the magnesium or alkaline earth salts of the corresponding nitroalcohols so obtained in aqueous suspension.

The novel antimicrobial compositions of the invention are comprised of an effective amount of at least one salicylic acid ester of Formula I and a major amount of an inert carrier. Preferably, the compositions contain 0.05 to 5% especially 0.1 to 1%, by weight of the total composition of the said esters. The compositions may be in the form of liquid, pasty or solid composition form, such as for example, aqueous suspensions, emulsions, solutions in organic solvents or oils, ointments, creams, pencils or powders, which may be used as cleaning preparations generally and specific skin-care preparations and other cosmetic preparations.

The novel method of killing fungi and bacteria comprises contacting fungi and/or bacteria with a lethal amount of at least one salicylic acid ester of Formula I.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 2-bromo-2-nitrobutyl salicylate 99 g. of 2-bromo-2-nitrobutanol-(l) were dissolved in cc. of benzene and after the addition of 78 g. of salicylic acid chloride, the mixture refluxed for 4 hours. The residue remaining after evaporation of the benzene was fractionally distilled in vacuo to obtain 131 g. (82.5% yield) of 2-bromo-2-nitrobutyl salicylate having a boiling point of 139 at'0.01 mm. Hg and a refractive index n =l.5499'.

EXAMPLE II least '21 days. Therefore, it was ascertained'wliic'h of the bstance concentrations worked into the culture media Usingthe procedure of Example I, 2-bromo-2-nitro w I t a propanol-(l) was reacted with salicylic acid chloride to Was Just abciut f the f obtain z bromo z nitmpropyl salicylate germs comp ete y. is va ue t us ascertaine was III. 1-

cated as threshold concentration. The tests were carried EXAMPLE I I out in the following concentration intervals: 10,000,

5,000, 2,500, 1,000, 750,500, 250, 100,;50, 25,110, 5, 2,5, 1, 0.5, 0.25 and 0.1 p.p.m.

Using the procedure of Example I, 2-bronio-2-nitro- The test organisms'used inithe platetest were propanediol-(l,3) was reacted with salicylic acid chloride to obtain 2-bromo-2-nitro-3-hydroxypropyl salicylate.

EXAMPLE IV 1=Staphyl0c0ccus aureits 2=Escherichia coli Using the procedure of Example I, l-bronio-l-nitro- 3=Pseudomonas aeruginosa 3,3,3-trichloropropanol-(2) was reacted with salicylic acid chloride to obtain 2-bromo-2-nitro-l-trichloromethyl 52:52:32? Kaufmanmwblf ethyl salicylate.

EXAMPLE V 6 Aspergzllus nzger I 7 Using the procedure of Example I, 2-bromo-2-nitro- In the Plate test the inhibiting coflcentfafiODS given in butanol-( 1) was reacted with salicylic acid chloride to Table I were found. obtain 2-bromo-2-nitrobutyl salicylate. 90 In addition, varying amounts of the three testcom. e pounds were administered to groups of mice in order to EXAMPLE VI determine LD dose in gm./kg. and these values are Using the procedure of Example I, 3-bromo-3-nitroreported in the last column of Table I.

TABLE L-INHIBITING CONCENTRATIONS IN P.P.M.

Test organlsm 1 2 3 4 s 1 e ilitia i5;

Substance: A 50 50 50 1 ,1 2.80 10,000 10, 000 10, 000 100 10,000 .1... 100 1,000 10 100 t 0.158

I butanol-(2) was reacted with salicylic ailid chloride to The results reported in Table I show that compound A obtain 2-bromo-2-nitro-1-methyl-propyl s icylate. of the invention has an activity 100 to 200 times greater than the corresponding salicylate ester B of the prior art EXAMPLE VII and is 10 to 20 times more active than the free bromo- To dem nstrate th adva tage f the salicylate esters nitro alcohol 0 while being more than 15times less toxic of Formula I as Compared with the Prior art salicylate to mice resulting in a much greater range of safety. and the corresponding free bromonitro alcohol, the activity of 2-b10mO-2-nitr0butYl salicylate (compound A) was COMPOSITION EXAMPLES compared with 2-nitro-buty1 salicylate (compound B) and 2-bromo-2-nitro-butanol-(l) (compound C). (A) A ti i bim l ti The inhibiting concentrations of the compounds examined were determined by the so-called plate test. This Parts by W test is a modified form of the dilution test for the estimasallcylate tion of the microbiostatic action described under the spmms to Q methods for the preliminary examination of such materials in the Instructions for the testing of chemical (B) Annmlcmbml ii by weight disinfectants of the Deutschen Gesellschaft fiir Hygiene (1) 2 bromo 2 nitropmpyl salicylate and Mikrobiologie, and can be advantageously used in Vaseline alba 100 yar ous tests instead of the use of liqu d culture med a (2) 2 bromo 2 nitro 1.t -ich]0r0methyl-cthyl' indicated therein. The advantage of sohd culture media salicylate obviously lies especially in tests of the activity of sub- Ungentum gg gi' gfigg T 100 stances towards fungl' (3) 2-bromo-2-nitro-3-hydroxypropyl salicylate 1 The desired test concentrations were prepared by mixpolyethylene glycol 300 and polyethyleneglycol ing specific amount of the substance solutions of suit- 1500 1;1 to 100 able concentrations with specific amounts of liquid bouil- (4) Lbromoamitromowl salicylate 1 Ion or beer wort-agars, in sterile petri-dishes. The Decyl oleate 16 amounts, measured with a pipette, of the substance solu- Colloidany dispersed mixture f 90 parts f C16 tions were a maximum of 0.1 to 1 ml. and the total to C18 alcohol and 10 parts f Sodium (11F. N volume in the petri-dishes after admixing with the culture C18 alcohol lf t media amounted to 10 ml. After solidification of the Water 60 culture media, its surface was inoculated with the test v v 1 germ suspension in bouillon or wort, which contained (C) A i i bi l powder about 10 germs per ml. The incubation took place at 37 Parts byweight C. or at 30 C. in the incubator, and lasted 8 days when 2 b 2 it b t 1 li l t 1 bacteria or Candida albicans were employed. When T l venet to 100 epidermophyton Kaufmann-Wolf were used, it lasted 21 a a 1' days. The duration of incubation of 21 days for epider- (D) Clear antiseptic shampoo I mophyton Kaulrnann-Wolf was chosen to conform to the Parts by weight above standard test, because in the evaluation of dis- 2-bromo-2-nitropropyl salicylate 3 infectants against fungi of the epithelium a substance is Sodium lauryl ether sulfate (27-28% 'WA'S) 40 considered as suitable when the growth of the fungi Coconut fatty acid diethanolamide. 6

after predetermined duration of action is delayed by at Water .n 51

(E) Deodorant spray Parts by weight 2-octyldodecanol l 2-bromo-2-nitrobutyl salicylate 2 Perfume 1 Ethanol 87 Propellant gas 100 (F) Deodorant pencil Parts by weight Stearyl alcohol 2-octyldodecanol 10 Coconut fatty acid monoethanolamide 10 Stearic acid monoethanolamide Carnauba wax 2 Parafiin 72 C. 11 Perfume oil 2 1,2-propylene glycol 38 2-bromo-2-nitrobutyl salicylate 2 (G) Disinfectant hand washing paste Parts by weight Sodium lauryl sulfate 52 Coconut fatty acid monoethanolamide 3 Finely ground pumice 42 2-bromo-2-nitrobutyl salicylate 3 (H) Antimicrobial fine washing composition Parts by weight Dodecylbenzenesulphonate 30 Toluenesulfonate 2 Sodium coconut fatty alcohol sulfate 8 Sodium sulfate I 30 Sodium carboxymethylcellulose 1 2-bromo-2-nitrobutyl salicylate 3 Water 26 (I) Foam bath Parts by weight 2-bromo-2-nitrobutyl salicylate 0.5 Sodium lauryl ether sulfate (27-28% WAS) 70. Coconut fatty acid diethanolamide 5.0 Water 25.0

Various modifications of the compositions and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims.

We claim:

1. A salicylic acid ester of the formula References Cited Coleman et al., Chem. Abst., 38 2967.

LORRAINE H. WEINBERGER, Primary Examiner J. F. TERAPANE, Assistant Examiner US. Cl. X.R. 

